Decoding the Genetic Basis of Alzheimer's Disease: A Comprehensive Review of Key Causal and Risk Genes, Pathological Mechanisms, Convergent Pathways, and Emerging Therapeutic Targets

Genetic and physiological basis of Alzheimer’s disease: A review

The current understanding of the genetic and physiological mechanisms underlying Alzheimer’s disease is reviewed and modern approaches for diagnosis and treatment are discussed.

Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease

Alzheimer’s Disease and Cognitive Disorders: From Molecular Drivers to Multilevel Clinical Solutions

Abstract Alzheimer’s disease (AD) represents the leading cause of dementia worldwide, accounting for approximately 70% of all dementia cases, and is characterized by progressive cognitive decline arising from complex interactions among molecular, genetic, environmental, and systemic factors. This review integrates current mechanistic insights with evolving diagnostic and therapeutic approaches. Central pathogenic processes include amyloid-β (Aβ) aggregation, tau hyperphosphorylation and propagation, neuroimmune dysregulation, synaptic failure, and network-level circuit disruption. Genetic and epigenetic contributors such as APOE genotype, aging-related inflammatory signaling, oxidative stress, and lifestyle-associated risk factors further modify susceptibility and disease trajectory. Recent advances in fluid biomarkers, amyloid and tau molecular imaging, and digital phenotyping—such as AI-driven cognitive assessments, gait analysis, voice analytics, and passive activity monitoring—have improved early detection and patient stratification. Emerging therapeutic strategies include disease-modifying agents, neuroprotective interventions, neurotrophin mimetics, and hormesis-based lifestyle approaches such as structured exercise, caloric modulation, and intermittent fasting. Precision-medicine trial designs and biomarker-guided therapeutic selection are transforming clinical research. At the clinical and public health level, caregiver-centered care models, community-based support systems, and multidomain prevention strategies emphasize the need for equitable, culturally informed dementia care. Future progress will depend on large-scale, diverse cohort studies, multi-omics integration, single-cell brain atlases, and AI-supported neuropathology pipelines to enable prevention and intervention during the preclinical window. This review highlights the importance of bridging mechanistic research with real-world clinical practice to generate impactful diagnostic, therapeutic, and policy outcomes. Keywords: Alzheimer’s disease, amyloid-β and tau pathology, neurodegeneration, biomarkers and digital phenotyping, precision medicine.  

Shared Metabolic–Proteinopathy Axis in Alzheimer's Disease and Parkinson's Disease: Evidence for a Convergent but Not Identical Disease Spectrum

ABSTRACT Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative disorders globally and have long been classified as clinically and pathologically distinct syndromes. AD is defined by amyloid‐β (Aβ) plaques and tau‐positive neurofibrillary tangles, whereas PD is characterized by α‐synuclein aggregation and progressive degeneration of nigrostriatal dopaminergic neurons. However, mounting evidence has blurred the traditional boundaries between these disorders, revealing extensive overlaps in pathogenic cascades, clinical phenotypes, and epidemiological risk factors. In this review, we propose an integrated mechanistic framework in which AD and PD represent distinct yet partially overlapping disorders along a convergent neurodegenerative spectrum, unified by a core metabolic–proteinopathy axis. We highlight cerebral insulin resistance and impaired brain glucose metabolism as pivotal upstream triggers that initiate a cascade of pathological events, including mitochondrial dysfunction, energy depletion, oxidative stress, chronic neuroinflammation, and disrupted proteostasis. These disturbances collectively drive aberrant folding and aggregation of Aβ, tau, and α‐synuclein, establishing a mechanistic link between systemic metabolic dysregulation and region‐selective neuronal vulnerability. We synthesize evidence from molecular studies, preclinical models, clinicopathological analyses, neuroimaging, and longitudinal epidemiological surveys to delineate the extent and limitations of mechanistic convergence. We also emphasize consistent divergences between AD and PD, including distinct patterns of neuroanatomical involvement, dominant clinical presentations, pathological propagation trajectories, and genetic architectures. Epidemiological data confirm that Type 2 diabetes and insulin resistance are associated with elevated risk of both AD and PD. Moreover, antidiabetic agents such as GLP‐1 receptor agonists exhibit convergent neuroprotective efficacy in preclinical and early clinical investigations, supporting metabolic modulation as a promising cross‐disease therapeutic strategy. Despite shared downstream pathways and therapeutic targets, AD and PD retain unique pathological signatures and clinical progression patterns. This review provides a balanced, evidence‐based interpretation of the AD–PD relationship, highlighting partial pathogenic convergence driven by metabolic dysfunction while affirming their identities as distinct disorders. The proposed metabolic–proteinopathy framework advances mechanistic understanding and informs the development of novel disease‐modifying therapies targeting shared upstream pathways.

Mechanisms and Intervention Strategies of Beta-Amyloid and Tau Proteins in Alzheimer's Disease

The synergistic pathological network between Aβ and tau is clarified, updated progress on targeted therapies are summarized, and theoretical support for accurate early diagnosis and individualized clinical treatment of AD is offered.

Alzheimer’s Disease in the Era of Geroscience: Mechanisms, Biomarkers, and Therapeutic Prospects

Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit.